The neurotrophins, including nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5), are among the molecular determinants that regulate the generation of diverse cell populations, especially neuronal cells and the maintenance of their functions within the nervous system, and many other cell types.
Neurotrophins are synthesized as precursors, called pro-neurotrophins, that are processed by proteolytic cleavage into their mature forms. The interaction of pro-neurotrophins with their receptors results in activation of death-pathways in many cell types.
In addition to regulating the life, function and/or death of neurons, the neurotrophins and pro-neurotrophins also regulate the development and viability of non-neuronal cell populations in skin, vascular endothelium, vascular pericytes, hair follicles, corneal epithelium, gut epithelium, retinal cells, glial cells, astrocytes, lymphocytes, and others. Neurotrophins and pro-neurotrophins have also been implicated or associated with several forms of cancer such as neuroblastoma, medulloblastoma, breast cancer, prostate cancer, and others.
All the mature neurotrophins and the pro-neurotrophins interact with the p75 receptor, a promiscuous receptor which binds to these 8 ligands (the 4 mature neurotrophins and their corresponding pro-neurotrophins). The p75 receptor belongs to the tumor necrosis factor (TNF) receptor superfamily. Neurotrophin binding takes place at the extracellular domain of p75, reportedly at the third and fourth cysteine loops.
The mature neurotrophins also bind more specifically to a receptor tyrosine kinase, called Trk (i.e., NGF binds to TrkA, BDNF and NT-4/5 bind to TrkB, and NT-3 binds to TrkC). These interactions trigger a cascade of known signals in the cell.
The TrkA, TrkB and TrkC receptors are expressed in neuroblastoma, medulloblastoma, breast cancer, prostate cancer, lymphoma, and other types of cancer cells.
In the CNS, cholinergic neurons express TrkA, dopaminergic neurons express TrkB, and retinal ganglion cells express TrkA and TrkB. In the PNS, motor neurons express TrkC, and sensory neurons express TrkA. Most of these neuronal populations also express the p75 receptor (also referred to as “p75”). Co-expression of p75 and a trk receptor on the same cell causes a “cross-talk” between the receptors; that is, there is a functional cross-regulation of one receptor upon the other. The cross-talk depends on the ligands engaging each receptor, and on the relative ratio of each receptor expressed on the cell surface.
Besides cells co-expressing both receptors or Trk receptors alone, there are many cell types that express p75, such as skin, vascular endothelium, vascular pericytes, hair follicles, corneal epithelium, gut epithelium, and pigmented epithelium; retinal cells such as glial cells, Muller cells, and photoreceptor cells; brain cells such as neurons, astrocytes and glia; and also lymphocytes and other cell types.
There is a need for novel inhibitors of p75 receptor function and/or activation which can be used therapeutically for p75-associated disorders or conditions.